Current therapeutic strategies for breast cancer are mostly aimed at controlling malignant disease. In most cases, these strategies extend a patient's lifespan, but are rarely successful in stopping the cancer. I believe that by gaining an understanding of the molecular mechanisms involved in development of premalignant lesions and progression to malignant cancer, we will be able to devise strategies to treat breast cancer early when there is a greater chance for cure. All invasive breast cancers originate from epithelial cells, which in the normal breast are arranged with a distinct polarized organization within ducts and lobules. Changes in cell polarity and organization are a key criterion used by pathologists in grading cancers, supporting the notion that regulation of cell polarity and tissue organization is a critical component of cancer progression. However, very little is known about the molecular mechanisms that regulate changes in cell polarity. It is my belief that mechanisms by which polarity pathways are altered in cancer represent an untapped area of cancer cell biology that offers tremendous potential for discovery of novel strategies for early diagnosis and treatment to effectively eradicate invasive breast cancer. During the past funding period we discovered that ErbB2 directly interacts with the Par6/aPKC polarity complex. This pathway was required for the ability of ErbB2 to disrupt cell polarity and inhibit cell death, but was dispensable to induce cell proliferation. These results have identified two major roles for polarity pathways in ErbB2 positive breast cancers - 1) to disrupt cell and tissue architecture; 2) to inhibit cell death. The latter was an unexpected finding, which was not predicted by all the studies previously performed in Drosophila and Worms. In this proposal we propose to extend on these finding and develop a deeper understanding of the mechanisms by which ErbB2 interacts with the polarity protein and identify the pathways downstream of ErbB2-Par6 polarity complex that regulates cell death. In the process of these studies we will develop robust in vivo models that will not only allow us to determine the in vivo relevance of our finding but will also function as tools for preclinical studies. In addition to the above, we also propose extend the scope and investigate how alterations in polarity pathways promote invasive progression and metastasis. Thus, I believe that our proposal takes an innovative strategy and exploits an unexplored area of cancer biology with the goal of finding a new class of biomarkers and drug targets.